A novel mitochondrial DNA deletion in a patient with Kearns-Sayre syndrome: a late-onset of the fatal cardiac conduction deficit and cardiomyopathy accompanying long-term rGH treatment

Abstract

BackgroundKearns-Sayre Syndrome (KSS) is a multisystem disorder caused by a dysfunction of the oxidative phosphorylation system within mitochondria. Mitochondrial DNA (mtDNA) rearrangements are a key molecular feature of this disease, which manifest a broad phenotypic spectrum.Case presentationHere, we present a boy with KSS whose symptoms included cardiac conduction deficit, cardiomyopathy and growth hormone (GH) deficiency. The patient showed typical symptoms for KSS from early childhood (chronic progressive external ophthalmoplegia, retinopathy, short stature). Long-range PCR analysis disclosed a 7663-base pair heteroplasmic deletion in the mtDNA encompassing nucleotides 6340–14003. At 12 years of age, GH deficiency was recognized and recombinant growth hormone (rGH) therapy was started. At 15 years of age, a complete atrioventicular block was diagnosed and the patient received a pacemaker. During the following 6 months, progressive deterioration of the left ventricle was observed and an echocardiogram showed features of dilated cardiomyopathy. The rGH treatment was then discontinued at a final height of 163 cm. Unfortunately, due to multi-organ insufficiency and inflammation, the patient died at the age of 18 years.ConclusionsThe response to rGH therapy in the patient was very satisfactory. The large mtDNA deletion had no apparent impact on the response to rGH. Cardiac disturbances occurred as part of the syndrome and were not related to rGH therapy; however, the progression of the disease led to death.

A case of hypopituitarism accompanying Kearns-Sayre syndrome treated with human chorionic gonadotropin: A case report and literature review

“…The patient was diagnosed with KSS based on the typical pathological results and clinical manifestations. Previous reports have described endocrine disorders, including insulin‐dependent diabetes mellitus, hypothyroidism, hypoparathyroidism and nonautoimmune Addison's disease, accompanying KSS (Holloman et al., ; Obara‐Moszynska et al., ; Quade et al., ), but there are no reports of their coexistence in a male with KSS.…”

“…KSS is caused by mtDNA rearrangements, and more than 150 different mtDNA deletions have been found to cause this syndrome (Holloman et al., ; Obara‐Moszynska et al., ). However, no mtDNA mutation was detected in blood cells collected from this patient.…”

“…He refused long‐term rGH therapy due to the lack of a significant effect on growth. One report has described a very satisfactory improvement in height velocity with rGH therapy in a boy with Kearns–Sayre syndrome accompanied by GH deficiency (Obara‐Moszynska et al., ). Some studies have demonstrated positive effects of rGH on the myocardium and on dilated cardiomyopathy (Perrot, Ranke, Dietz, & Osterziel, ).…”

Mitochondrial disease and endocrine dysfunction

“…Growth hormone deficiency has been described in multiple case reports and case series with MELAS [10,[49][50][51][52][53], decreased complex II activity [54], mtDNA deletion disorders [12,13,[55][56][57][58], and various mitochondrial diseases without genetic confirmation [59,60]. Growth hormone deficiency and/or short stature has also been documented in nuclear-encoded defects of mitochondrial translation, e.g.…”

Association between the mitochondrial DNA 4977 common deletion in the hair shaft and hearing loss in presbycusis

“…Cochlea tissue is rich in mtDNA, which have a high probability of deletion. The deletions in mtDNA in cochlea tissue have been shown to include mtDNA 13162, 10422, 7663, 7436, 4989 and 4977 bp deletions, with the mtDNA CD4977 being the most common in cochlea tissue (7)(8)(9)(10)(11)(12).…”